The overall goal of this Program is to develop novel stem cell transplantation and gene therapy approaches to produce an intact immune system in patients with Severe Combined Immune Deficiency (SCID) and other Primary Immune Deficiencies. The manipulation of stem and progenitor cells in the profoundly immune deficient patient with SCID provides a unique biological and clinical setting to unravel mechanisms of stem cell engraftment, lymphopoiesis and immune reconstitution. The central hypothesis of the Program is that the age of the hematopoietic graft and the host environment influences the ultimate reconstitution of the immune system in the patient with SCID. Each of the Projects will test this hypothesis from a different and complementary perspective. The goal of Project 1 is to delineate the role of the thymic vascular niche in the regulation of homing and engraftment of bone marrow cells to the neonatal thymus after bone marrow transplantation (BMT). Project 2 will provide new information regarding fetal and adult B cell development and the development of the humoral immune response, with a specific focus on the ontogeny of B-1 B cells. This information will be highly relevant to understanding the restoration of humoral immunity following BMT and gene therapy. The goal of Project 3 is to develop more effective and safer approaches to treat SCID patients using in vivo ADA gene delivery, an approach that our data suggests will be most successful during the neonatal period and early infancy. The Program brings together an experienced and collaborative team of investigators from CHLA, UCLA and UC Davis. Two scientific cores will support the Projects by providing specialized expertise in cell and tissue isolation and analysis and in animal models of transplantation and gene therapy. When brought together, these Projects and Cores will provide synergy and focus for basic and clinical studies in Stem Cell therapies for SCID, the most lethal form of Primary Immune Deficiency. Relevance to Public Health: Young infants possess a unique biology that makes them more responsive to stem cell and gene therapy aimed at restoring the immune system. Understanding the mechanisms that afford this developmental advantage may lead to improved approaches for immune disorders in older children and adults.